Targeting anticoagulant protein S to improve hemostasis in hemophilia.

Prince Eladnani, Raja; Bologna, Luca; Manetti, Mirko; Melchiorre, Daniela; Rosa, Irene; Dewarrat, Natacha; Suardi, Silvia; Amini, Poorya; Fernández, José A; Burnier, Laurent; Quarroz, Claudia; Reina Caro, Maria Desiré; Matsumura, Yasuhiro; Kremer Hovinga, Johanna Anna; Griffin, John H; Simon, Hans-Uwe; Ibba-Manneschi, Lidia; Saller, François; Calzavarini, Sara and Angelillo, Anne (2018). Targeting anticoagulant protein S to improve hemostasis in hemophilia. Blood, 131(12), pp. 1360-1371. American Society of Hematology 10.1182/blood-2017-09-800326

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Improved treatments are needed for hemophilia A and B, bleeding disorders affecting 400,000 people worldwide. We investigated whether targeting protein S could promote hemostasis in hemophilia by re-balancing coagulation. Protein S is an anticoagulant acting as cofactor for activated protein C and tissue factor pathway inhibitor (TFPI). This dual role makes PS a key regulator of thrombin generation. Here, we report that targeting protein S rebalances coagulation in hemophilia. Protein S gene targeting in hemophilic mice protected them against bleeding, especially when intra-articular. Mechanistically, these mice displayed increased thrombin generation, resistance to activated protein C and TFPI, and improved fibrin network. Blocking protein S in plasma of hemophilia patients normalized in vitro thrombin generation. Both protein S and TFPIα were detected in hemophilic mice joints. Protein S and TFPI expression was stronger in joints of hemophilia A than hemophilia B patients when receiving on demand therapy, e.g., during a bleeding episode. In contrast, protein S and TFPI expression was decreased in hemophilia A patients receiving prophylaxis with coagulation factor concentrates, and comparable to osteoarthritis patients. These results establish protein S inhibition as both controller of coagulation and potential therapeutic target in hemophilia. The murine protein S silencing RNA approach that we successfully used in hemophilic mice might constitute a new therapeutic concept for hemophilic patients.

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